CL-140980
Received: October 24, 2014 | Accepted: November 12, 2014 | Web Released: February 5, 2015
Flash Chemistry Using Trichlorovinyllithium:
Switching the Reaction Pathways
by High-resolution Reaction Time Control
Aiichiro Nagaki, Yusuke Takahashi, Andrea Henseler, Chika Matsuo, and Jun-ichi Yoshida*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering,
Kyoto University, Nishikyo-ku, Kyoto 615-8510
(E-mail: yoshida@sbchem.kyoto-u.ac.jp)
H
High-resolution reaction time control in flow microreactors
Cl
Cl
Li
Cl
Cl
n-BuLi
- LiCl
n-BuLi
Cl
Cl
Li
Cl
Cl
enables the reaction-pathway switching of trichlorovinyllithium
generated by the H/Li exchange of trichloroethene. The method
was successfully applied to the synthesis of 1,1,2-trichloroalkenes,
1-chloroalkynes, and unsymmetrically disubstituted ethynes.
Cl
Cl
E1
E1
E1
E1
Cl
Cl
Cl
s-BuLi
Li
E1
E2
The development of reactions in which one set of starting
materials results in the selective formation of different compounds
at will has attracted significant interest in recent organic
chemistry.1 If one set of starting materials gives more than one
compound by simply changing the reaction conditions, the method
provides a powerful tool in organic synthesis. In particular, the
effective use of biomass materials is one of the most prominent
examples of such cases.2 Herein we show that flash chemistry3
using flow microreactors4-6 is effective for switching reaction
pathways to give different products at will.
Recently, flow microreactors have received significant re-
search interest from both academia and industry, because they are
expected to make a revolutionary change in chemical synthesis and
production. For example, flow microreactors are advantageous for
reactions that involve unstable short-lived reactive intermediates.7
Unstable intermediates can be transferred to another location to be
used in the next reaction before they decompose by virtue of their
extremely short residence time in flow microreactors. Therefore,
many chemical conversions that are impossible in macro batch
reactors have been successfully accomplished using flow micro-
reactors (flash chemistry).
E1
E2
Figure 1. Synthesis of chloroalkenes and alkynes from trichloro-
ethene.
Table 1. H/Li exchange of trichloroethene with n-BuLi followed by
reaction with benzaldehyde in a batch macroreactor
n-BuLi
(x equiv)
PhCHO
(3.00 equiv)
OH
H
Cl
Cl
Li
Cl
Ph
Ph
Cl
Cl
Cl
10 min
60 min
Cl
Cl
Cl
HO
Cl
2
1
Yield/%a
Temperature
x/equiv
/°C
1
2
¹78
1.05
2.00
1.05
2.00
0
0
0
0
44
89
48
75
0
aDetermined by GC analysis with an internal standard.
Carbon-carbon triple and double bonds frequently occur in a
variety of organic molecules and the development of new, versatile
methods for the synthesis of alkenes and alkynes has still received
significant research interest. Reactions of 2-halovinylmetals serve
as powerful methods for this purpose.8,9 Especially, 2-halovinyl-
lithiums are attractive intermediates because of their high
reactivity compared to other 2-halovinylmetals.10 Direct reactions
with electrophiles give alkenes and the elimination of lithium
halides gives alkynes, but the control of β-elimination is often
problematic. We have recently, however, found that the elimi-
nation of LiCl from trans-1,2-dichlorovinyllithium, which is
generated by the H/Li exchange of trans-1,2-dichloroethene, was
successfully controlled by adjusting the residence time in flow
microreactors.11 Either direct reaction with an electrophile, to give
substituted 1,2-dichloroethenes, or the β-elimination followed by
the reaction with an electrophile, to give substituted ethynes,
was performed selectively at will. We envisaged that the use of
trichlorovinyllithium should also be useful for similar trans-
formations.12 Notably, the starting material, trichloroethene, is
much cheaper than trans-1,2-dichloroethene. However, to the best
of our knowledge, such studies have not been reported so far,
presumably because of the difficulty in the control of β-elimination
of LiCl from trichlorovinyllithium. In this paper we report that the
reaction pathways of trichlorovinyllithium generated by the H/Li
exchange of trichloroethene can be switched at will based on high-
resolution reaction time control in flow microreactors to obtain
1,1,2-trichloroalkenes and 1-chloroalkynes after reaction with
electrophiles (Figure 1). The chlorine functionality in the products
can be used for further transformation. For example, the Cl/Li
exchange of 1-chloroalkynes followed by reaction with electro-
philes enables the synthesis of unsymmetrically disubstituted
ethynes (Figure 1).
First, we examined the H/Li exchange of trichloroethene with
n-BuLi (1.05 or 2.00 equiv) followed by reaction with benzalde-
hyde in a conventional batch macroreactor. As shown in Table 1,
2,3,3-trichloro-1-phenylprop-2-en-1-ol (1) was not obtained at all.
A significant amount of 3-chloro-1-phenylprop-2-yn-1-ol (2) was
produced in all cases, presumably because of the extremely
fast elimination of LiCl from trichlorovinyllithium under these
conditions.
© 2015 The Chemical Society of Japan